Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/80—[b, c]- or [b, d]-condensed
  • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention is concerned with certain aminosubstituted tetrahydrobenzindoles, their preparation and pharmaceutical use.
• the compounds have pharmacological activity, e.g. antihypertensive, prolactin inhibition, anti-Parkinson agent.
• alkyl of 1 to 3 carbon atoms methyl, isopropyl and ethyl are preferred.
• the monosubstituted phenyl groups are chlorophenyl, iodophenyl, methoxyphenyl isopropoxyphenyl and n-propylphenyl.
• Examples of the (mono)substituted phenyl-C l -C 3 -alkyl group are benzyl, bromophenyl-C 3 H 6 ⁇ , ethoxyphenyl-C 2 H 4 ⁇ and methylphenyl-CH 2 ⁇ .
• the preferred monosubstituted phenyl group is the same as that defined above.
• the term halogen includes Br, Cl, F and iodo with Br, CI and F being preferred and Br and CI being more preferred.
• An example for R 3 is OCH 3 .
• the pharmaceutically acceptable salts are the salts of Formula I with suitable inorganic or organic acids.
• suitable organic acids are carboxylic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, pamoic acid, pivalic acid and oxalic acid and non carboxylic acid such as isethionic acid and naphthalene disulfonic acid.
• useful inorganic acids are the hydrohalides such as HCI and HBr, H 2 SO 4 and phosphoric acid.
• C l -C 3 alkyl is preferably methyl and R 2 is H.
• R is CH 3 and R', R 2 and R 3 are all H.
• Another class of preferred compounds has the formula III
• R 2 is H.
• R is phenyl and R', R 2 and R 3 are all H.
• the compounds of the present invention are active antihypertensives.
• a representative compound was tested in a protocol using a spontaneously hypertensive (SH) rat model to demonstrate this activity. This test indicates that the present compounds would be useful in treating hypertension in hypertensive human patients.
• SH spontaneously hypertensive
• the compounds of the present invention are administered to the hypertensive patient by any convenient mode of administration e.g. orally or parenterally using appropriate dosage e.g. tablets, emulsions, solutions, capsules for oral administration and solutions, suspensions, emulsions for parenteral administration.
• appropriate dosage e.g. tablets, emulsions, solutions, capsules for oral administration and solutions, suspensions, emulsions for parenteral administration.
• Conventional procedures are used to prepare suitable pharmaceutical compositions in proper dosage forms using conventional, pharmaceutically acceptable diluents, compounding ingredients, and the like.
• Sufficient amount of a compound of the present invention is administered to the patient to produce the desired therapeutic effect i.e. lowering of high blood pressure.
• Suitable dosages will thus vary and the daily dosage in humans may range from about 10 mg. to about 3000 mg., preferably about 20 mg. to about 1000 mg. and more preferably about 50 mg. to about 500mg.
• the present compounds also have other pharmacological properties which make them useful in humans as prolactin inhibitors or for treating Parkinson's disease, at appropriate dosages and using appropriate modes of administration e.g. parenterally or orally.
• the compounds of the present invention may be prepared by any available process.
• a convenient process useful for this preparation is illustrated by the following set of equations: the term “tos” stands for the tosylate or p-tolylsulphonyl moiety.
• the compound A is known [see Bowman et al., J. C. S. Perkin I, 438 (1973)].
• Treatment of A with 1 suitable anhydride or acyl halide introduces the substituent on the amino N (compound B).
• the ketone group adjacent to the amino group is then thioketalized by treatment with 1,3-propanedithiol and trimethylsilylchloride in chloroform using conventional conditions to yield the C product.
• the thioketal group is removed by treatment with a suitable catalyst such as Raney nickel to yield compound D.
• the product (D) obtained is then hydrogenated using an appropriate system such as lithium aluminum hydride to yield the desired final product E.
• Step A 4-Acetamino-1,3,4,5-tetrahydro-1-(p-tolylsulphonyl)benz[c,d]indol-5-one
• a heterogeneous mixture of 4-amino-1,3,4,5-tetrahydro-1-(p-tolylsulphonyllbenz[c,d]indol-5-one hydrochloride (10 gm) and acetic anhydride (100 ml) is heated on a steam bath until homogeneity is achieved (15 minutes).
• the reaction mixture is poured with stirring into water (650 ml).
• the solid is filtered and dried in a steam oven to yield 9.5 gm of 4-acetamino-1,3,4,5-tetrahydro-1-(p-tolylsulphonyl)benz[c,d]indol-5-one, m.p. 180-185°.
• Step 8 4-Acetamino-1,3,4,5-tetrahydro-1-(p-tolylsulphonyl)benz[c,d]indol-5-one(2,3-propylenedithioacetal)
• Step C 4-Acetamino-1,3,4,5-tetrahydro-1-(p-tolylsulphonyl)benz[c,d]indole
• Step D 4-N-Ethylamino-1,3,4,5-tetrahydrobenz[c,d]indole
• the compound (ii) may be converted to the corresponding compound where the group in the 8- position is OH by suitably cleaving the OCH 3 group by using e.g. trimethylsilyl iodide [see J. Org. Chem. 42, 3761 ⁇ 3764 (1977)].
• Halogenation of the tetrahydrobenzindole moiety in the 2-position can be carried out using the process described in von F. Troxler in Helv. Clinc. Acta 40, 2160 (1957).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)
• Steroid Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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Publications (3)

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Cited By (5)

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• 1979
  • 1979-11-23 US US06/096,948 patent/US4282240A/en not_active Expired - Lifetime
• 1980
  • 1980-11-19 DE DE8080107188T patent/DE3069381D1/de not_active Expired
  • 1980-11-19 AT AT80107188T patent/ATE9690T1/de not_active IP Right Cessation
  • 1980-11-19 EP EP80107188A patent/EP0029581B1/en not_active Expired
  • 1980-11-20 GR GR63410A patent/GR72131B/el unknown
  • 1980-11-21 DK DK497680A patent/DK497680A/da not_active Application Discontinuation
  • 1980-11-21 ES ES497063A patent/ES8203343A1/es not_active Expired
  • 1980-11-21 PT PT72088A patent/PT72088B/pt unknown
  • 1980-11-25 JP JP16476980A patent/JPS5687562A/ja active Granted

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